- 作者：Ognen Ivanovski ; Igor G. Nikolov ; Nobuhiko Joki ; Axelle Caudrillier ; Olivier Phan ; Romuald Mentaverri ; Julien Maizel ; Yasuhiro Hamada ; Thao Nguyen-Khoa ; Masafumi Fukagawa ; Said Kamel ; Bernard Lacour
- 关键词：Calcimimetics ; Uremia ; Calcification ; Calcium-sensing receptor ; FGF23 ; Atherosclerosis ; ApoE− ; /− ; mouse
- 刊名：Atherosclerosis
- 出版年：2009
- 出版时间：July 2009
- 年：2009
- 卷：205
- 期：1
- 页码：55-62
- 全文大小：1482 K
ObjectiveSecondary hyperparathyroidism of chronic kidney disease promotes vascular calcification. Calcimimetics reduce serum parathyroid hormone, calcium (Ca), and phosphorus by calcium-sensing receptor (CaR) activation. Here we examined possible effects of the calcimimetic R-568 (R-568) on the progression of aortic calcification and atherosclerosis in apoE−/− mice with chronic renal failure (CRF) and the potential implication of aortic smooth muscle cell CaR.Methods and results
ApoE−/− mice were assigned to 3 CRF groups and 1 non-CRF group receiving daily gavage with R-568, calcitriol, or vehicle. Serum Ca and phosphorus and parathyroid gland volume of CRF mice were decreased by R-568, whereas elevated serum FGF23 and total cholesterol remained unchanged. Both aortic plaque and non-plaque calcification was lower in R-568 mice, and so was atherosclerotic plaque area fraction. In vitro, R-568 induced a decrease in smooth muscle cell calcification when cultured in high phosphate medium. This decrease was abolished in CaR-SiRNA-transfected cells.
Conclusions
The calcimimetic R-568 delayed the progression of both aortic calcification and atherosclerosis in uremic apoE−/− mice. This effect was mediated via a better control of hyperparathyroidism including serum Ca and phosphorus. Direct vascular CaR activation also could have played a role in the observed effects.